The objectives of this U19 proposal are to design and synthesize highly potent and specific small-molecule inhibitors of Bcl-2/Bcl-xL. We will test these inhibitors in vitro and in vivo to determine their therapeutic potential in prostate cancer animal models. Our central rationale/ hypothesis is that (1) hormone-refractory prostate cancer cells with high levels of Bcl-2/Bcl-xL proteins depend upon the protection of Bcl-2/xL for survival advantage and so become resistant to chemotherapeutic agents;(2) inhibition of the anti-apoptotic function of Bcl-2/xL using a potent, cell-permeable small-molecule inhibitor may overcome chemoresistance and improve the efficacy of current chemotherapy, representing a highly effective and novel strategy for the treatment of hormone-refractory prostate cancer by overcoming apoptosis-resistance. To test our hypothesis, we propose to carry out three interrelated Specific Aims: Aim 1: To evaluate the in vitro anti-tumor activity of the most potent and promising Bcl-2 small-molecule inhibitors and investigate their mechanism of action in apoptosis induction;Aim 2: To evaluate the in vivo anti-tumor activity of the most potent and promising Bcl-2/xL inhibitors;Aim 3: To evaluate the Bcl-2 family of proteins in a VCaP model during tumor progression/transition from androgen sensitive to insensitive prostate cancer and the therapeutic potential of Bcl-2/xL inhibitors in overcoming chemoresistance of the androgen independent VCaP. Successfully carried out, our in vitro and in vivo studies will provide the important proof-of-concept that a highly potent and specific small-molecule inhibitor of Bcl-2/xL may have a great therapeutic potential to be developed as a new and effective therapy for treating hormone-refractory prostate cancer, alone and in combination with chemotherapy by overcoming apoptosis-resistance. This will provide the critical impetus to bring the best Bcl-2/xL small-molecule inhibitor to advanced preclinical development and future clinical studies as an entirely new class of cancer therapy.